The ability of cells to invade and migrate from the primary tumor site and subsequently survive within distal microenvironments forms the basic mechanisms underlying cancer progression and are the major cause of cancer-related morbidity and mortality. Altered interactions between mitogenic hormones, growth factors, and the extracellular matrix (ECM) are considered to be among the more important factors contributing to cancer progression (Beattie et al., 2010). One such growth factor family is the insulin-like growth factor (IGF) system, members of which have well documented roles in the development and progression of numerous malignancies, including breast cancer (Annunziata et al., 2011; Fox et al., 2011). The IGFs are also tightly regulated by a family of specific binding proteins, termed insulin like growth factor binding proteins (IGFBPs; IGFBPs 1-6), whose primary role is to bind free IGFs and thereby moderate their half-life, specificity and activity. The IGF system includes the IGF receptor type-1 (IGF-1R) which is a transmembrane receptor with tyrosine kinase activity. IGF-1R mediates proliferation when activated by the stimulatory ligands IGF-I and IGF-II (Dupont and LeRoith, 2001). The insulin receptor is also a key component of the IGF signaling pathway. Although the classic insulin receptor isoform-B (IR-B) binds only insulin and elicits insulin-related metabolic effects, insulin receptor isoform-A (IR-A) binds IGF-II in addition to insulin and initiates mitogenic signaling (Pandini et al., 2002). An important feature of the IGF system, including the expression of IGF-1R, is its ubiquitous presence in most carcinomas (Boone and Lee, 2012). For example, in breast cancer, IGF-1R expression is found in nearly 90% of tumors (Bonneterre et al., 1990; Nielsen et al., 2004), with over expression of IGF-1R observed in 44% of breast cancer tissue specimens (Shimizu et al., 2004). Apart from increased expression levels, the role of IGF-1R signaling in malignant transformation and in tumor cell proliferation makes it an attractive therapeutic target.
There have been several reports, both in vitro and in vivo, targeting IGF-1R activation using various strategies, including antisense technology (Schillaci et al., 2006), dominant negative IGF-1R (Sachdev et al., 2004), small molecule chemical inhibitors (Blum et al., 2003; Garcia-Echeverria et al., 2004; Haluska et al., 2006) and inhibitory antibodies, an approach most frequently used (Sachdev et al., 2003; Cohen et al., 2005). Indeed, more than 70 clinical trials across 30 candidate drugs have been tested, with a few currently progressing through phase-II, in a wide variety of human malignancies (Gombos et al., 2012). Most trials have used antibodies and small molecule inhibitors for the therapeutic blockade of IGF-1R including the fully human monoclonal antibodies cixutumumab (ImClone) and AMG-479 (Amgen). The IGF-1R antagonizing monoclonal antibodies currently used are very specific owing to the specific epitope recognition within the IGF-1R and demonstrate no binding to the insulin receptor. This is designed to overcome concerns of the off-target induction of insulin resistance and hyperglycemia driven by cross-targeting the IR-B (Haluska et al., 2007). However, monoclonal antibodies targeting only the IGF-1R will have no inhibitory effects on IR-A-mediated signaling. This could be a potential liability if IR-A or Hybrid IGF-1R/IR receptor (HyR)-mediated signaling can overcome the IGF-1R blockade (Pandini et al., 2002), given that excess circulating levels of IGF-I and IGF-II can signal through IR-A or HyR after anti-IGF-1R therapy (Huang et al., 2009). This could be potentially subverted by the use of tyrosine kinase inhibitors which are currently in clinical and preclinical development (e.g., BMS-536924 and BMS-554417 (Bristol-Myers Squibb)). A particular disadvantage of tyrosine kinase inhibitors is that these therapies indiscriminately inhibit the kinase domains of all IGF system receptors, including the IR-A and -B, since the primary sequences of IGF-1R and IRs share near absolute conservation in the kinase domains (Munshi et al., 2003). In spite of their advantages of potentially inhibiting the IR-A-mediated compensatory effects on IGF-1R blockade, these broad spectrum inhibitors will also inhibit the IR-B receptor which may represent a significant liability on insulin metabolism. Recently, a few tyrosine kinase inhibitors have been developed, namely NVP-AEW541 and NVP-ADW742 (Novartis), and BVP.51004 (Biovitrium) that have been shown in cellular assays to selectively inhibit only IGF-1R kinases and not the IR kinases. Nevertheless, no clinical data are available on these inhibitors to date. Furthermore, no therapies yet exist in the clinic that can demonstrate the combined benefits of IGF-1R-specific and tyrosine kinase therapies. In summary, current therapies are associated with insulin resistance or IR-A-mediated compensations seen in the IGF-1R-specific therapies, or disregulated insulin metabolism seen in the broad-spectrum tyrosine kinase therapies.
Hence, there is a need to develop novel modulators that block the activation of the tumorigenic receptors within the IGF system whilst simultaneously permitting the normal insulin signaling to occur through the IR-B receptor.